Medicine delivery is an important aspect of medical treatment. The efficacy of many medicines is directly related to the way in which they are administered. Some therapies require that the medicine be repeatedly administered to the patient over a long period of time. This makes the selection of a proper medicine delivery method problematic. Patients often forget, are unwilling, or are unable to take their medication. Medicine delivery also becomes problematic when the medicines are too potent for systemic delivery. Therefore, attempts have been made to design and fabricate a delivery device that is capable of the controlled, periodic or continuous release of a wide variety of molecules including, but not limited to, drugs and other therapeutics.
Micro-electro-mechanical system (MEMS) technology integrates electrical components and mechanical components on a common silicon substrate using microfabrication technology. Integrated circuit (IC) fabrication processes, such as photolithography processes and other microelectronic processes, form the electrical components. The IC fabrication processes typically use materials such as silicon, glass, and polymners. Micromachining processes, compatible with the IC processes, selectively etch away areas of the IC or add new structural layers to the IC to form the mechanical components. The integration of silicon-based microelectronics with micromachining technology permits complete electromechanical systems to be fabricated on a single chip. Such single chip systems integrate the computational ability of microelectronics with the mechanical sensing and control capabilities of micromachining to provide smart devices small enough to be implanted inside of a human or animal.
Examples of implantable medicine delivery systems suitable for fabrication using micro-electro-mechanical system (MEMS) technology are described in U.S. Pat. No. 5,366,454 (Currie, et al.), and U.S. Pat. No. 6,123,861 (Santini, Jr., et al.). These patents are described as improvements over non-MEMS type of electromechanical devices that are larger and less reliable and controlled release polymeric devices, designed to provide medicine release over a period of time via diffusion of the medicine through the polymer and/or degradation of the polymer over the desired time period following administration to the patient.
U.S. Pat. No. 5,366,454 (Currie, et al.) discloses a medication dispensing device for implantation into an animal or human body, and including a substrate having a plurality of compartments, a closure member, a rupturable membrane and a membrane rupturing system. Each compartment has a charging opening for charging the compartment with a dose of medicine and a delivery opening permitting delivery of the medicine. The closure member, made of silicon, is anodically bonded to the substrate, also made of silicon, for sealing the charging openings of the compartments. The membrane, made of silicon, may be integrally formed with the substrate or anodically bonded to the substrate, also made of silicon, for sealing the delivery openings of the compartments. The membrane has a predetermined elastic deformation limit and a predetermined rupture point. A “V-shaped” groove is formed in the membrane to define a line of weakness to assist the rupture of the membrane. The membrane rupturing system associated with each compartment ruptures the membrane thereof in response to an electrical signal. The membrane rupturing system includes a stress-inducing member maintaining the membrane stressed to substantially the elastic deformation limit thereof, and a piezoelectric transducer responsive to the electrical signal for applying to the membrane additional stress sufficient to exceed the rupture point of the membrane, thereby causing the membrane to rupture. Upon rupture of the membrane, body fluids are permitted to enter into the compartment for mixing with the medicine contained therein so that the medicine is released in admixture with the body fluids through the delivery opening into the animal or human body. The device further includes a control circuit connected to a power source for supplying the electrical signal to a respective piezoelectric transducer of each membrane rupturing system to activate the respective piezoelectric transducer. A biologically compatible polymeric film covers the membrane to bind any broken membrane fragments to the device and to prevent the fragments from being released into the human or animal.
U.S. Pat. No. 6,123,861 (Santini, Jr., et al.) discloses a microchip drug delivery device for controlling the rate and time of delivery of molecules, such as medicines, in either a periodic or continuous manner. This device typically includes hundreds to thousands of reservoirs, or wells, formed in a silicon substrate containing the molecules and a release element that controls the rate of release of the molecules. The reservoirs can contain multiple medicines or other molecules in variable dosages. The filled reservoirs can be capped with materials that passively disintegrate, materials that allow the molecules to diffuse passively out of the reservoir over time, or materials that disintegrate upon application of an electric potential. Release from an active device can be controlled by a preprogrammed microprocessor, remote control, or by biosensors.
Several methods are used to bond silicon wafers together or to other substrates, such as glass substrates, to form larger or more complex micromachined systems, such as medicine delivery systems, including: adhesion bonding, anodic bonding, eutectic bonding, glass-frit bonding, fusion bonding, low temperature fusion bonding, and microwave bonding. Among these various bonding methods engineering tradeoffs exist for the applied temperature, applied voltage, applied pressure, applied energy, bonding time, bond strength, material cost, etc.
Adhesion bonding uses an adhesive to bond the substrates together. This is typically done by spin coating a thin film of adhesive on one or both substrates before they are brought into contact. The substrates are typically baked at a prescribed temperature to cure the adhesive.
Anodic bonding, otherwise known as electrostatic bonding, typically hermetically and permanently joins glass to silicon substrates without using adhesives. The glass substrate contains typically has a high percentage of alkali metals, such as sodium oxide. The silicon and glass substrates are brought into contact with each other. The silicon and glass substrates are heated to a temperature (typically in the range 300-500° C. depending on the glass type) above the softening point of the glass substrate that results in the sodium oxide splitting up into sodium and oxygen ions. A high DC voltage (e.g., up to 1 kV) is applied across the substrates creating an electrical field that penetrates the substrates. The electric field causes the sodium ions to migrate from the interface between the substrates towards the cathode where they are neutralized providing a depletion layer with high electric field strength. The resulting electrostatic attraction at the depletion layer brings the silicon and glass into intimate contact. The electric field also causes the oxygen ions to flow from the glass substrate to the silicon substrate resulting in an anodic reaction at the interface with the silicon ions in the silicon substrate to form irreversible silicon-oxygen-silicon bonds. The result is that the glass substrate is bonded to the silicon substrate with a permanent chemical bond. The disadvantages of anodic bonding include the relatively high temperature required, temperature non-uniformity during vacuum sealing, and relatively long bond times (e.g., 10 minutes).
Eutectic bonding and glass-frit bonding use a film of metal and glass ceramic adhesive, respectively, to hermetically seal the substrates together under high temperature.
Fusion bonding uses two silicon substrates having hydrophobic or hydrophilic, mirror-polished, flat and clean surfaces. The two surfaces of the substrates contact each other under high pressure creating atomic attraction forces that bond the two substrates together. The atomic attraction forces are strong enough to allow the bonded substrates to be moved to a furnace. The bonded substrates are annealed at high temperature (e.g., 900° C.-1100° C.) in the furnace to form a solid hermetic seal between the two substrates.
Low temperature fusion bonding advances the glass-frit bonding process. In contrast to the glass-frit bonding process, low temperature fusion bonding does not use a glass ceramic adhesive to bond the substrates together. The low temperature fusion bonding process uses low heat to soften the substrates, and pressure to squeeze and hold the substrates together until they bond over a prescribed period of time.
Microwave bonding uses electromagnetic energy to bond two metallized dielectric or silicon substrates to each other. The electromagnetic energy in the form of a pulse heats the metallic interface between the two substrates to melt the interface together while permitting the substrates to remain cool.
It would be desirable to have a medicine delivery system, adapted to be implanted in a human or animal, that actively releases a drug or other molecule into the animal or human by rupturing a membrane, without permitting the ruptured membrane to separate from the medicine delivery system and to be released in the animal or human. Such a system would not permit disintegrated membrane material to separate from the drug delivery device to be released in the animal or human, as disclosed in U.S. Pat. No. 6,123,861 (Santini, Jr., et al.). Further, such a system would not require the biologically compatible polymeric film shown as necessary by U.S. Pat. No. 5,366,454 (Currie, et al.) to bind any broken membrane fragments to the device and to prevent the fragments from being released into the human or animal.
It would also be desirable to have a bonding process to hermetically seal two substrates together at a temperature lower than the 300-500° C. range used for anodic bonding. Such a bonding process would not damage thermally degraded materials, such as the medicine in the medication dispensing device as disclosed in U.S. Pat. No. 5,366,454 (Currie, et al.). Such a bonding process would also be fast to provide high manufacturing throughput. Further, such a process would also apply a relatively low pressure to the substrates.